SUMMARY Visceral leishmaniasis (VL) is a significant parasitic disease in the north-east of India. It is caused by the intracellular protozoan parasite Leishmania donovani and is characterized by immune dysfunction that can result in VL patients being more susceptible to secondary infections. There is no effective vaccine to prevent or treat VL, and current drug treatment is undermined by cost, toxicity and the potential development of drug-resistant parasites. We will measure the frequency and activation status of key immune cells including T cells and monocytes, in the blood, bone marrow and skin of VL patients before, during and after drug treatment. In addition, we will characterize transcriptional and metabolic signatures in these cell populations to identify novel molecules to target for therapeutic advantage or to identify individuals likely to relapse or develop disease complications. In addition, we will test whether specific immune responses against parasite antigens can be used to identify individuals with asymptomatic infections. There is a great need to better understand host immune responses in VL patients. The identification of immune markers that detect T cells and/or monocytes that have recently encountered parasite antigen in our studies will allow us to monitor and measure parasite burden amongst populations in VL endemic regions, and would represent a major achievement for this Project, as well as providing a valuable diagnostic tool for VL elimination Programs. We will work with colleagues in Project 1 to identify asymptomatic individuals for immune studies, as well as to identify novel markers that can be used to identify these individuals who would not normally be recognized by conventional means of detection. In addition, work on Phlebotomine sand fly vectors conducted in Project 2 will help guide experiments aimed at better understanding immune responses in the skin proposed in this project. For example, we will investigate the influence of the local immune environment in the skin on the ability of the host to transmit infection to a sand fly. Thus, our Project not only focuses on the impact of VL on the host, but also on transmission and maintenance of disease in the region, and as such, will generate important complimentary data for other Projects within the Program. Elimination of VL is considered an achievable goal, and the work proposed in this Project will help to achieve this. Our research also has direct implications and applications for many diseases because the immunoregulatory and metabolic pathways we study are likely to be present in other chronic diseases, and our discoveries will thus have broad applications in medicine.